Abs1166 Effect of Silymarin Against Methotrexate-induced Liver Injury in Rheumatic Diseases, a Pilot Double-blind Randomized Controlled Trial
Year: 2025
Type: conference-abstract
Abstract: Background: Methotrexate (MTX) is a commonly used immunosuppressant for treating rheumatic diseases. It may result in treatment discontinuation due to hepatotoxicity. Silymarin (SMN) is a traditional medicine, with several trials showing its beneficial hepatoprotective properties. However, for MTX-induced hepatotoxicity, its use remains promising. Objectives: To investigate the effect of SMN in the prevention of hepatotoxicity in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) who were initiating treatment with MTX. Methods: The study was a 12-week, single center, double-blind, placebo (PBO)-controlled, randomised pilot trial. Eligible patients were at least 20 years old and diagnosed with active RA or PsA who initiated MTX within 30 days prior randomisation. The participants were randomly assigned in a 1:1 ratio to receive either SMN 140 mg orally three times a day or PBO for 12 weeks. The primary endpoint was the proportion of patients with elevated serum aspartate transaminase (AST) and/or alanine transaminase (ALT) above the upper limit of normal (ULN) throughout the 12-week study period. The secondary endpoints included the elevated serum AST/ALT ≥ 3 times the ULN, the elevated serum AST or ALT > 2 times from baseline, MTX discontinuation, disease activity and adverse events (AEs). As part of this assessment, the planned sample size was 72 participants. The randomised participants were analysed as intention to treat principle. Results: Between 31 January to 30 September 2024, 27 patients were included in the study (RA; n=19, PsA; n=8). The patients were assigned to the SMN group (n=12) and the PBO group (n=12). Both groups exhibited comparable baseline characteristics. The proportion of patients with elevated serum AST/ALT above the ULN was similar between groups (1 versus 1 patient). Nevertheless, one patient in the PBO group had elevated serum AST/ALT ≥ 3 times the ULN and stopped MTX treatment. The SMN group demonstrated a greater reduction in disease activity (the Disease Activity Score-28 with CRP; -2.42 versus -1.54; p-value = 0.14) and lower incidence of AEs (15% versus 21%; p-value = 1.00) compared to the PBO group, although these differences did not reach statistical significance. Conclusion: This pilot study indicated that 12 weeks of SMN intake did not show a hepatoprotective effect against MTX-induced hepatitis. Considering the small sample size, large-scale studies are needed to assess this finding. Trial registration: ClinicalTrials.gov, NCT06277635. REFERENCES: NIL . Table 1Baseline demographics and disease related features in the study population according to treatment group (n=24).VariablesSilymarin group(n=13)Placebo group(n=14)P-valueAge at enrollment (year), mean (SD)56.76 (12.91)54.42 (11.94)0.62Female, n (%)9 (69.23)10 (71.42)1.00BMI (kg/m2), mean (SD)22.66 (3.52)24.99 (3.97)0.12Alcohol drinking, n (%)2 (15.38)00.22Comorbidities, n (%)- Diabetic mellitus1 (7.69)1 (7.14)1.00- Dyslipidemia3 (23.07)4 (28.57)1.00- Hypertension1 (7.69)2 (14.28)1.00Diagnosis, n (%)- Rheumatoid arthritis11 (84.61)8 (57.14)0.21- Psoriatic Arthritis2 (15.38)6 (42.85)0.21Duration of disease (years), median (IQR)0 (0, 2.31)0 (0, 1.6)0.81Disease activity at enrollment, mean (SD)*- DAS 28 CRP5.16 (2.05)4.76 (1.71)0.62Treatment at enrollment, n (%)- NSAIDs6 (46.15)5 (35.71)0.58- Prednisolone3 (23.07)3 (21.42)1.00- Statin3 (23.07)1 (7.14)0.32- Paracetamol2 (15.38)5 (35.71)0.38Average methotrexate dose at 12 weeks, (mg/wk), mean(SD)14.23±2.1314.10±4.550.92Liver function tests at baseline, mean (SD)- AST (IU/L)21.46 (4.15)18.46 (3.01)0.04- ALT (IU/L)19.15 (9.37)15.92 (7.27)0.33- TB (mg/dl)0.47 (0.25)0.35 (0.18)0.25- ALP (IU/L)92.08 (22.94)77.11 (18.68)0.12CRP (mg/L), median (IQR)35 (18.46)41.53 (18.93)0.40*DAS 28 CRP for rheumatoid arthritis and psoriatic arthritis.BMI, body mass index; DAS, disease activity score; ESR, erythrocyte sedimentation rate: CRP, C reactive protein; AST, aspartate aminotransferase; ALT, alanine aminotransferase; TB, total bilirubin; ALP, alkaline phosphatase. Table 2Primary and secondary outcomes at 12 weeks across treatment groups (ITT analysis).Silymarin group(n=13)Placebo group(n=14)P-valuePrimary endpoint:AST or ALT > 1X ULN, n (%)1 (7.69)1 (7.14)1.00Secondary endpoints:AST or ALT > 2X from baseline, n (%)3 (23.07)3 (21.42)1.00AST or ALT > 3X ULN, n (%)01 (7.14)1.00AST or ALT > 5X ULN or > 3 ULN with symptom of hepatitis or TB >2X ULN with jaundice, n (%)00-Adverse events, n (%)2 (15.38)3 (21.42)1.00Methotrexate discontinuation, n (%)01 (7.14)1.00Change of DAS 28 CRP, median (IQR)*-2.42 (-3.61, -1.43)-1.54 (-2.29, -0.63)0.14*Changes of DAS28 CRP at 12 weeks compared to baseline.ITT, intention-To-Treat; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ULN, upper limit normal; TB, total bilirubin; DAS, disease activity score; ESR, erythrocyte sedimentation rate; CRP, C reactive protein. Acknowledgements: This study was funded by the Phramongkutklao Hospital Foundation. Disclosure of Interests: None declared . © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.
Source: Annals of the Rheumatic Diseases
Institutions: Phramongkutklao Hospital, Phramongkutklao College of Medicine
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,870
OpenAlex ID: W4411410268